Citations

Inadequate light penetration in tissues restricts photodynamic therapy to treating only superficial tumors. To enable x-ray–excited photodynamic therapy (XPDT) that targets deep-seated tumors, we synthesized a nanoscintillator-photosensitizer complex containing 5% Eu-doped Y 2 O 3 fluorescing at 611 nanometers and decorated with SiO 2 containing the scintillation-coupled photosensitizer methylene blue and a polyethylene glycol coating [PEGylated Y 2 O 3 :Eu@SiO 2 -methylene blue (pYSM)]. When irradiated, pYSMs generate singlet oxygen species in vitro, causing cytotoxicity with hallmarks of immunogenic cell death (calreticulin translocation to the cell membrane). Intravenously administered pYSMs home passively to pancreatic tumor xenografts and, upon 10 gray irradiation, cause significant tumor regression ( P < 0.01). On combining XPDT with anti-PD1 immunotherapy, a distant nonirradiated tumor also regresses via an increase in intratumoral activated CD8 + cytotoxic T cells. Collectively, we advance a systemically delivered XPDT strategy that mediates an antitumor effect in both irradiated and nonirradiated (abscopal) tumors when coupled with immunotherapy, converting an immunologically “cold” tumor to an immunologically “hot” tumor.

Abstract Introduction: Individuals with cancer may be at higher risk of atrial fibrillation (AF). However, sufficient data are lacking in AF risk among breast cancer survivors, especially for the mid-to long-term risk of AF and the impact of cancer treatment on this association. We aimed to investigate the risk of incident AF in women diagnosed with breast cancer and evaluate the association by length of follow-up and breast cancer treatment. Methods: Using the Korean Health Insurance Service database, we studied 96,476 women who were diagnosed with breast cancer (aged≥20 years) without prior history of AF and breast cancer and underwent breast cancer surgery between January 2007 and December 2013. They were matched 1:3 to a cancer-free population (n=289,428) based on birth year and sex and were followed to the end of 2018. Using ICD-10 codes (I48.0 to I48.4, I.48.9), AF was defined when it was a discharge diagnosis or was verified more than twice in an outpatient clinic. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of AF associated with breast cancer relative to the cancer-free population, adjusting for age, income, and comorbidities including diabetes, hypertension and hyperlipidemia. Results: During a median follow-up of 6.8 years, AF developed in 2,105 women with breast cancer (3.2 per 1,000 person-years). Mean age at baseline among participants was 49.6 years. Having breast cancer was associated with increased risk of AF (HR, 2.04; 95% CI, 1.93-2.15). This association was stronger for women aged &lt;50 years (HR, 3.98; 95% CI, 3.59-4.40). When we repeated analyses with lag periods of two years to explore the possibility of reverse causation and mid-to long-term risk of AF (n=91,370), the association was largely attenuated but remained significant (HR, 1.18; 95% CI, 1.09-1.28 for total women and HR, 1.60; 95% CI, 1.38-1.86 for women aged &lt;50 years). However, no increased risk of AF was observed in women with breast cancer aged &gt;65 years. Compared with no use of anthracyclines and taxanes, respectively, ever use of anthracyclines and taxanes was associated with increased risk of AF after further adjusting for other cancer treatment modalities including use of trastuzumab, radiotherapy, and endocrine treatment (HR, 1.25; 95% CI, 1.12-1.40 and HR, 1.37; 95% CI, 1.23-1.53, respectively). This association persisted only among women with breast cancer ever treated with anthracyclines when analysis was limited to those with two year-lag periods (HR, 1.23; 95% CI, 1.04-1.45). Conclusions: In this large-scale nationwide cohort study in South Korea, women with breast cancer had an elevated risk of incident AF, especially for women with breast cancer younger than 50 years, regardless of the length of follow-up. Our findings also suggest that cardiotoxic side effects of cancer treatment such as use of anthracyclines might increase both short-term and mid-to long-term risk of AF among women with breast cancer. Citation Format: Yong-Moon ("Mark") Park, Wonyoung Jung, Yohwan Yeo, Sang Hyun Park, Ronda Henry-Tillman, Hong Seok Lee, Tasneem Z. Naqvi, Kyungdo Han, Dong Wook Shin. Risk of atrial fibrillation among women diagnosed with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3214.

Sarcopenia, a syndrome commonly seen in elderly populations, is often characterized by a gradual loss of skeletal muscle, leading to the decline of muscle strength and physical performance. Growing evidence suggests that the prevalence of sarcopenia increases in patients with heart failure (HF), which is a dominant pathogenesis in the aging heart. HF causes diverse metabolic complications that may result in sarcopenia. Therefore, sarcopenia may act as a strong predictor of frailty, disability, and mortality associated with HF. Currently, standard treatments for slowing muscle loss in patients with HF are not available. Therefore, here, we review the pathophysiological mechanisms underlying sarcopenia in HF as well as current knowledge regarding the beneficial effects of exercise on sarcopenia in HF and related mechanisms, including hormonal changes, myostatin, oxidative stress, inflammation, apoptosis, autophagy, the ubiquitin-proteasome system, and insulin resistance.

Abstract Membrane curvature is closely associated with spatial distribution of lipids and curvature can influence the formation of lipid rafts in biological membranes. However, it is still unclear how the curvature elasticity plays a role on the asymmetric distribution of lipids across the membrane leaflets, especially, during the process of the raft domain growth. Using supported lipid membranes on wedge‐shaped substrates with alternating positive and negative curvatures, curvature‐mediated asymmetry of lipid raft domains is observed across the membrane leaflets accompanied by glycolipid receptor (GM 1 and GT 1 b) localization. The raft domains initially appear only in a membrane leaflet possessing negative curvatures. In the presence of the interleaflet coupling, they evolve to generate the transverse registry across the membrane bilayer. It is shown that a human recombinant antibody rHIgM12 is co‐localized with the rafts formed at the peaks and valleys of the wedge substrate, indicating that the spatial distribution of its receptor (GT 1 b) is indeed manifested by the site‐specific formation of asymmetric raft domains through the curvature elasticity. The platform can be used to explore the mechanism for the leaflet asymmetry and lipid sorting in terms of the membrane curvature, the composition, and the receptor presentation.

Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neurologic disease that primarily affects spinal cord anterior horn cells and their axons for which there is no treatment. Here we report the use of a recombinant natural human IgM that binds to the surface of neurons and supports neurite extension, rHIgM12, as a therapeutic strategy in murine models of human ALS. A single 200 µg intraperitoneal dose of rHIgM12 increases survival in two independent genetic-based mutant SOD1 mouse strains (SOD1G86R and SOD1G93A) by 8 and 10 days, delays the onset of neurologic deficits by 16 days, delays the onset of weight loss by 5 days, and preserves spinal cord axons and anterior horn neurons. Immuno-overlay of thin layer chromatography and surface plasmon resonance show that rHIgM12 binds with high affinity to complex gangliosides GD1a and GT1b. Addition of rHIgM12 to neurons in culture increases α-tubulin tyrosination levels, suggesting an alteration of microtubule dynamics. We previously reported that a single peripheral dose of rHIgM12 preserved neurologic function in a murine model of demyelination with axon loss. Because rHIgM12 improves three different models of neurologic disease, we propose the IgM may act late in the cascade of neuronal stress and/or death by a broad mechanism.